Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation

High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefi...

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Autores principales:	Ying Jin, Xueqin Chen, Zizheng Gao, Xiaofei Shen, Huangxi Fu, Zezheng Pan, Hao Yan, Bo Yang, Qiaojun He, Zhifei Xu, Peihua Luo
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Apoptosis Autophagy Bisdemethoxycurcumin Cutaneous toxicity Vandetanib Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a7701ad358b54f8f823a938022ffeebe
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spelling	oai:doaj.org-article:a7701ad358b54f8f823a938022ffeebe2021-11-14T04:29:21ZBisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation0753-332210.1016/j.biopha.2021.112297https://doaj.org/article/a7701ad358b54f8f823a938022ffeebe2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221010817https://doaj.org/toc/0753-3322High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established an in vivo model by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rash in vivo, which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0–10 μM, 0–24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagy in vivo and in vitro, thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.Ying JinXueqin ChenZizheng GaoXiaofei ShenHuangxi FuZezheng PanHao YanBo YangQiaojun HeZhifei XuPeihua LuoElsevierarticleApoptosisAutophagyBisdemethoxycurcuminCutaneous toxicityVandetanibTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112297- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Apoptosis Autophagy Bisdemethoxycurcumin Cutaneous toxicity Vandetanib Therapeutics. Pharmacology RM1-950
spellingShingle	Apoptosis Autophagy Bisdemethoxycurcumin Cutaneous toxicity Vandetanib Therapeutics. Pharmacology RM1-950 Ying Jin Xueqin Chen Zizheng Gao Xiaofei Shen Huangxi Fu Zezheng Pan Hao Yan Bo Yang Qiaojun He Zhifei Xu Peihua Luo Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
description	High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established an in vivo model by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rash in vivo, which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0–10 μM, 0–24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagy in vivo and in vitro, thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.
format	article
author	Ying Jin Xueqin Chen Zizheng Gao Xiaofei Shen Huangxi Fu Zezheng Pan Hao Yan Bo Yang Qiaojun He Zhifei Xu Peihua Luo
author_facet	Ying Jin Xueqin Chen Zizheng Gao Xiaofei Shen Huangxi Fu Zezheng Pan Hao Yan Bo Yang Qiaojun He Zhifei Xu Peihua Luo
author_sort	Ying Jin
title	Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
title_short	Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
title_full	Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
title_fullStr	Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
title_full_unstemmed	Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
title_sort	bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/a7701ad358b54f8f823a938022ffeebe
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Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation

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